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Despite earlier promise, latency-reversing strategy designed to mop up tiny reservoirs of HIV doesn’t work with current compounds

Newswise — Scientists at Johns Hopkins report that compounds they hoped would “wake up” dormant reservoirs of HIV inside immune system T cells — a strategy designed to reverse latency and make the cells vulnerable to destruction — have failed to do so in laboratory tests of such white blood cells taken directly from patients infected with HIV.

“Despite our high hopes, none of the compounds we tested in HIV-infected cells taken directly from patients activated the latent virus,” says Robert F. Siliciano, M.D., Ph.D., a professor of medicine at the Johns Hopkins University School of Medicine and a Howard Hughes Medical Institute investigator.

Siliciano is senior author of a report on the disappointing results published online March 23 in Nature Medicine.

The failure challenges the idea that a single so-called latency-reversing agent can uncover the HIV hiding out in the cells of patients whose viral load is essentially undetectable with blood tests.

While inactive, the dormant HIV lurks in the cells but does not replicate in the amounts needed to produce proteins that can be recognized by the immune system. Without that recognition, the immune system cannot eliminate the last remaining HIV from the body. Current treatment with antiretroviral drug regimens known as HAART (highly active antiretroviral therapy) does not target the dormant HIV.

Studies have long demonstrated that these tiny reservoirs can be rekindled if a patient stops taking medication, a phenomenon that has proven to be the major barrier to a cure.

Laboratory models of latent HIV-infected cells suggested that certain compounds, mostly a group of drugs called HDAC inhibitors, might reverse the latency and awaken the infected cells just enough to make them vulnerable to eradication, Siliciano says. These inhibitors affect the genetic operation of viruses and have also been used in drugs that treat cancer and some neurological disorders.

The strategy depends on reactivating the very few remaining HIV reservoirs while HAART is in use, so that the infected cells will be eliminated while HAART prevents any new cells from becoming infected. The dormant virus is found in roughly one of every million white blood cells in someone with HIV. If all of the cells with latent HIV can be eliminated, Siliciano says, drug therapy can be safely stopped and the infection essentially cured.

Because cells with latent HIV are so rare and difficult to retrieve from infected people, researchers have used engineered latent HIV cell models to test HDAC inhibitors in the past, says study co-author Janet D. Siliciano, Ph.D., an associate professor of medicine at the Johns Hopkins University School of Medicine. Typical models have used white blood cells infected with HIV in a test tube that are then cultured until the virus becomes latent. Studies with HDAC inhibitors in these models worked very well.

For their new study, the Johns Hopkins team used a process called leukapheresis, in which a patient with HIV is hooked to a machine that removes blood and separates out the red and white blood cells, returning only the red blood cells to the body. By this method, the team collected a large enough sample of lymphocytes with latent HIV reservoirs to test the HDAC inhibitors on actual cells.The goal of the new study was to compare various latency-reversing agents against one another on these patient-derived cells to see which one was best at turning on the virus, says Greg Laird, a Ph.D. candidate at Johns Hopkins and also a study co-author. “The surprise was that none of them actually worked,” he says.

HDAC inhibitors were the major class of the latency-reversing agents studied by the Johns Hopkins team. HDAC proteins repress the production of RNA, a key step in taking the DNA’s blueprint and using it to create, in this case, the viral protein that comprises the business end of the virus and spurs its growth.

Despite the failure of HDAC inhibitors and other compounds in their study, Laird and another principal author, Korin Bullen, also a Johns Hopkins Ph.D. candidate, say the experiments led them to develop more sensitive assays to test for reactivation of the virus.

They also created a yardstick by which to judge future successes with perhaps other compounds or combinations of therapies: If a T cell is activated in an HIV-infected person, that cell produces virus at the maximum level, essentially the equivalent of a 100-fold increase in viral RNA production. Most of the drugs studied created a one- or two-fold increase; one resulted in a six- to 10-fold increase. (personal note: they mean Bryostatin-1)

The next step, the researchers say, is to study some of the drugs in combination using patient-derived cells, in hopes that the sum is greater than the parts.

The research was funded by the Collaboratory of AIDS Researchers for Eradication, the Delaney AIDS Research Enterprise, the National Institutes of Health’s National Institute of Allergy and Infectious Diseases (AI096113 and AI096109), The Foundation for AIDS Research (108165-50-RGRL and 108707-54-RKRL), the Johns Hopkins Center for AIDS Research and the Howard Hughes Medical Institute.

Christine Durand, M.D., of Johns Hopkins also contributed to this research.####

Johns Hopkins Medicine (JHM), headquartered in Baltimore, Maryland, is a $6.7 billion integrated global health enterprise and one of the leading health care systems in the United States. JHM unites physicians and scientists of the Johns Hopkins University School of Medicine with the organizations, health professionals and facilities of The Johns Hopkins Hospital and Health System. JHM's vision, “Together, we will deliver the promise of medicine,” is supported by its mission to improve the health of the community and the world by setting the standard of excellence in medical education, research and clinical care. Diverse and inclusive, JHM educates medical students, scientists, health care professionals and the public; conducts biomedical research; and provides patient-centered medicine to prevent, diagnose and treat human illness. JHM operates six academic and community hospitals, four suburban health care and surgery centers, and more than 30 primary health care outpatient sites. The Johns Hopkins Hospital, opened in 1889, was ranked number one in the nation for 21 years in a row by U.S. News & World Report."

I hate it to be such a Spoiler today But even if Gene Transfer or CalImmune or Sangamo should work, there is still the problem of the possible cancer risk caused by free-floating genetic snippets. I think that the FDA or the European Admission board will demand an observation phase of at least 10 or more years. This is what was heard on a HIV congress. So we have a lot of time for many new threads

"...health will finally be seen not as a blessing to be wished for, but as a human right to be fought for." Kofi Annan

Nymphomaniac: a woman as obsessed with sex as an average man. Mignon McLaughlin

HIV is certainly character-building. It's made me see all of the shallow things we cling to, like ego and vanity. Of course, I'd rather have a few more T-cells and a little less character. Randy Shilts

I hate it to be such a Spoiler today But even if Gene Transfer or CalImmune or Sangamo should work, there is still the problem of the possible cancer risk caused by free-floating genetic snippets. I think that the FDA or the European Admission board will demand an observation phase of at least 10 or more years. This is what was heard on a HIV congress. So we have a lot of time for many new threads

This is disappointing news. From what I remember, they developed a new assay, tested a lot of drugs, and found some promising candidates. The methodology seemed rigorous and exhaustive.

Well, I always thought it was a long shot that you'd be able to get every little virion. Those things are tiny.

I'm still thinking that Picker's idea is the best. Continually produce antibodies with a cross between CMV and HIV. Hopefully they'll figure out why it worked really well in some of the test animals and not as well in the others.

This leukapheresis...how did they know this lymphocytes have a latent virus or not since they only collected a sample of lymphocytes?...How could they conclude HDACi couldn't work since they didn't know exactly the cells infected or not?.

This is disappointing news. From what I remember, they developed a new assay, tested a lot of drugs, and found some promising candidates. The methodology seemed rigorous and exhaustive.

Well, I always thought it was a long shot that you'd be able to get every little virion. Those things are tiny.

I'm still thinking that Picker's idea is the best. Continually produce antibodies with a cross between CMV and HIV. Hopefully they'll figure out why it worked really well in some of the test animals and not as well in the others.

I agree with you, the Picker's vaccine is quite potent but it is only a Tcell vaccine and you need to create antibodies too... hence the antibody gene transfer of David Baltimore. Both can be combined, even if having a CMV vaccine is quite dangerous : we could be cured of HIV but have a cancer some years later...

But even if Gene Transfer or CalImmune or Sangamo should work, there is still the problem of the possible cancer risk caused by free-floating genetic snippets. I think that the FDA or the European Admission board will demand an observation phase of at least 10 or more years. This is what was heard on a HIV congress.

Hey, Matts...is this right? 10 years "observation"? While I guess it's not shocking that regulatory boards will be extremely cautious with any new technology like this, a ten year wait and see period after a verified cure is announced seems like a recipe for a whole lotta hell raising from the public. Can you direct me to an article or two that talks about this concept? Thanks.

I think it was Prof. Hauber (tre-recombinase) or Dr. Huetter on a radiointerview from a HIV congress, I dont find the link at the Moment, it was in German anyway.

I only have this link from Dr. Jacob P. Lalezari (Quest Clinical Research San Francisco) who says nearly the same :

"...The newly building up immune system would thus be permanently protected. With a possible risk: When the researchers cut a gene, and the cell is to glue together the two loose ends, the cell could become confused and ends somewhere else to go stick. This leads to a DNA rearrangement that may trigger cancer..."(translated from german)

Matts - Interesting. Cheers. I do believe though there are patients out there who have presumably had these "snippets" floating around in their systems for many years (10-15 +/-) as they were part of the Zinc Finger pre-clinical work of Dr. Carl June at the University of Pennsylvania. Regardless, it will be interesting to see how it plays out.

I think i heard in CROI 2014 presentation (some website has mp3 for it) that panobinostat was able to reduce reservoir in 4 out of 15 persons.i wonder the pathway for this apostosis. TRAIL, cox-2 or nfk-b related i guess. just like cpg7909 that also reduce the reservoir.

well, drugs is more simple and cheaper than broadly neutralizing antibody or gene theraphy.hope some drugs will works.